A key step in the synthesis of the reverse transcriptase inhibitor, (-)-6-chloro-4-cyclopropylethynyl-4-trifluoromethyl-1,4-dihydro-2H-3,1-ben zoxazin-2-one, also known as DMP-266, is the chiral addition to the 2-trifluoromethylcarbonyl-4-chloroaniline to give desired enantiomer of the amino alcohol in optically pure form.
The synthesis of DMP-266 and structurally similar reverse transcriptase inhibitors are disclosed in U.S. Pat. No. 5,519,021 and the corresponding PCT International Patent Application WO 95/20389, which published on Aug. 3, 1995. Additionally, the asymmetric synthesis of an enantiomeric benzoxazinone by a highly enantioselective acetylide addition and cyclization sequence that has been described by Thompson, et al., Tetrahedron Letters 1995, 36, 8937-8940, as well as the PCT publication, WO 96/37457, which published on Nov. 28, 1996.
Additionally, several applications have been filed which disclose various aspects of the synthesis of (-)-6-chloro-4-cyclopropylethynyl-4-trifluoromethyl-1,4-dihydro-2H-3,1-ben zoxazin-2-one including: 1) a process for making the chiral alcohol, U.S. Ser. No. 60/035,462, filed Jan. 14, 1997; 2) the chiral additive, U.S. Ser. No. 60/034,926, filed Jan. 10, 1997, U.S. Ser. No. 60/042,021, filed Apr. 17, 1997, U.S. Ser. No. 60/045,167, filed Apr. 30, 1997; 3) a cyclization reaction, U.S. Ser. No. 60/037,059, filed Feb. 12, 1997; 4) the anti-solvent crystallization procedure, U.S. Ser. No. 60/037,385 filed Feb. 5, 1997 and U.S. Ser. No. 60/042,807 filed Apr. 8, 1997; 5) a zinc-catalyzed enantioselective addition U.S. Ser. No. 60/046,713 filed May 16, 1997; and 6) a process for preparing cyclopropylacetylene, U.S. Ser. No. 60/047,692 filed May 23, 1997.
The instant invention discloses an efficient method for enhancing the optical purity of the amino alcohol: ##STR1##
The instant method allows one to enhance the optical purity of the amino alcohol regardless of the synthetic route used to make the amino alcohol. The previous methods used the protection of the amino group as a means for enhancing the enantiomeric excess of the desired R-amino alcohol. In the most recent process developments the protection deprotection sequence has been eliminated necessitating a means by which the enantiomeric excess amino alcohol could be upgraded.